A Convenient Procedure for Transformation of Tertiary Cyclopropanols into 5-Substituted Isoxazoles

Abstract

Tertiary cyclopropanols, when treated with an excess of amyl nitrite at room temperature, are smoothly converted into dimeric β-nitrosoketones. Heating the methanolic solutions of the latter under reflux gives 5-substituted isoxazoles in good yields.

Key words

cyclopropanols - nitrosation - β-nitrosoketones - isoxazoles - isoxazolines

References and Notes

• 1a Kulinkovich OG. Sviridov SV. Vasilevskii DA. Pritytskaya TS. J. Org. Chem. USSR (Engl. Transl.)  1989,  25:  2027 
• 1b Kulinkovich OG. Sviridov SV. Vasilevskii DA. Synthesis  1991,  234 
• 1c Kulinkovich OG. Savchenko AI. Sviridov SV. Vasilevsky DA. Mendeleev Commun.  1993,  230 
• 2 For recent review, see: Kulinkovich OG. Russ. Chem. Rev. (Engl. Transl.)  2004,  53:  1065 
• 3a Denis JM. Conia JM. Tetrahedron Lett.  1972,  13:  4593 
• 3b Le Goaller R. Pierre J.-L. Bull. Soc. Chim. Fr.  1973,  1531 
• 3c Rubotton GM. Lopes MI. J. Org. Chem.  1973,  38:  2097 
• 4a Ryu I. Murai S. In Houben-Weyl   4th ed., Vol. E17:  de Meijere A. Thieme; Stuttgart: 1996.  p.1985 
• 4b Kuwajima I. Nakamura E. Top. Curr. Chem.  1990,  133:  3 
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• 7a Kulinkovich OG. Chem. Rev.  2003,  103:  2597 
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• 16 Bellamy LJ. Advances in Infrared Group Frequencies   Methuen & Co. Ltd.; Bungay / Suffolk: 1968. 

11

Cyclopropanols 1a-h were synthesized by the reductive cyclopropanation of the corresponding esters with ethylmagnesium bromide (compounds 1a-g) or propylmagnesium bromide (1h) in the presence of titanium(IV) isopropoxide (see ref. 1).

12

Utilization of amyl nitrite that was stored in a refrigerator for more than two weeks led to a significant reduction of the reaction rate and to a decrease in the yields of products.

13

After crystallization from MeOH pure E isomer was obtained.

14

Preparation of β-Nitrosoketones 2; Typical Procedure: Freshly prepared amyl nitrite (17 mL, 124 mmol) was added at 5 °C under Ar atmosphere to a solution of 1a (4.9 g, 31 mmol) in anhyd benzene (5 mL) in one portion. The mixture was stirred for 3 h and was kept at r.t. until the reaction was completed as monitored by TLC (2-3 d, see ref. 20). The mixture was concentrated in vacuo and was used for the preparation of isoxazoles without further purification. In order to obtain solid samples of 2a (as a mixture of Z and E isomers), the residue was diluted with petroleum ether, cooled and the crystals were filtered off. Single E isomer of 2a (3.45 g, 20.2 mmol, 65%) was obtained by the crystallization from hot MeOH as a yellowish solid (mp 86-87 °C).

15

Analytical data of selected nitrosoketones 2.
2a: ¹H NMR (400 MHz, CDCl₃): δ = 0.83 (t, J = 6.8 Hz, 3 H), 1.18-1.30 (m, 6 H), 1.49-1.59 (m, 2 H), 2.44 (t, J = 7.4 Hz, 2 H), 2.90 (t, J = 6.2 Hz, 2 H), 4.40 (t, J = 6.2 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.84, 22.31, 23.41, 28.64, 31.39, 36.40, 42.74, 53.48, 206.63. IR (CCl₄): 1722, 1371, 1250 cm^-1. Anal. Calcd for C₉H₁₇NO₂ (171.24): C, 63.13; H, 10.01. Found: C, 63.28; H, 9.75.
2c: ¹H NMR (400 MHz, CDCl₃): δ = 2.04-2.13 (m, 2 H), 2.72 (t, J = 7.0 Hz, 2 H), 2.97 (t, J = 6.1 Hz, 2 H), 3.58 (t, J = 6.2 Hz, 2 H), 4.47 (t, J = 6.1 Hz, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.10, 36.69, 39.44, 44.21, 53.60, 205.58. IR (CCl₄): 1720, 1370, 1247 cm^-1. Anal. Calcd for C₆H₁₀ClNO₂ (163.61): C, 44.05; H, 6.16. Found: C, 43.90; H, 5.89.

17

Preparation of Isoxazoles; Typical Procedure: Crude β-nitrosoketone 2a, prepared from 1e (4.9 g, 31 mmol) and amyl nitrite (17.0 mL, 124 mmol) as described above (see ref. 14) was diluted with anhyd MeOH (45 mL). The solution was heated under reflux until TLC indicated that no β-nitrosoketone 2a and intermediate isoxazoline 4a remained (2-3 days, see ref. 20). After removal of the solvent under reduced pressure, the isoxazole 3a was isolated by column chromatography (SiO₂, PE-EtOAc as eluent) as a yellowish oil (4.4 g, 91%).

18

Analytical data of selected isoxazoles 3.
3c: ¹H NMR (400 MHz, CDCl₃): δ = 2.13-2.22 (m, 2 H), 2.97 (t, J = 7.4 Hz, 2 H), 3.57 (t, J = 6.3 Hz, 2 H), 6.03-6.05 (m, 1 H), 8.14-8.17 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 23.70, 30.14, 43.54, 100.58, 150.22, 170.93. IR (CCl₄): 1606 cm^-1. Anal. Calcd for C₆H₈ClNO (145.59): C, 49.50; H, 5.54. Found: C, 49.33; H, 5.75.
3e: ¹H NMR (400 MHz, CDCl₃): δ = 1.22-1.40 (m, 10 H), 1.65-1.73 (m, 2 H), 1.99-2.06 (m, 2 H), 2.76 (t, J = 7.7 Hz, 2 H), 4.92 (ddt, J ₁ = 10.2 Hz, J ₂ = 2.2 Hz, J ₃ = 1.1 Hz, 1 H), 4.98 (ddt, J ₁ = 16.9 Hz, J ₂ = 2.2 Hz, J ₃ = 1.5 Hz, 1 H), 5.80 (ddt, J ₁ = 16.9 Hz, J ₂ = 10.2 Hz, J ₃ = 6.7 Hz, 1 H), 5.95-5.97 (m, 1 H), 8.12-8.14 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 26.49, 27.49, 28.83, 28.98, 28.99, 29.11, 29.24, 33.73, 99.76, 114.13, 139.10, 150.12, 173.02. IR (CCl₄): 3079, 1640, 1593 cm^-1. Anal. Calcd for C₁₃H₂₁NO (207.32): C, 75.32; H, 10.21. Found: C, 75.59; H, 10.02.
3g: ¹H NMR (400 MHz, CDCl₃): δ = 1.16 (t, J = 7.0 Hz, 6 H), 3.09 (d, J = 5.7 Hz, 2 H), 3.29 (dq, J ₁ = 9.4 Hz, J ₂ = 7.0 Hz, 2 H), 3.66 (dq, J ₁ = 9.4 Hz, J ₂ = 7.0 Hz, 2 H), 4.78 (t, J = 5.7 Hz, 1 H), 6.09 (d, J = 1.6 Hz, 1 H), 8.14 (d, J = 1.6 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 15.06, 31.92, 61.91, 100.18, 101.56, 150.19, 168.18. IR (CCl₄): 2874, 1734, 1597, 1125, 1064 cm^-1. Anal. Calcd for C₉H₁₅NO₃ (185.22): C, 58.36; H, 8.16. Found: C, 58.60; H, 8.01.

19

Analytical data of 4: ¹H NMR (400 MHz, CDCl₃): δ = 0.88 (t, J = 6.9 Hz, 3 H), 1.22-1.53 (m, 8 H), 1.82-1.97 (m, 2 H), 2.89 (dd, J ₁ = 18.4 Hz, J ₂ = 1.3 Hz, 1 H), 2.92 (dd, J ₁ = 18.4 Hz, J ₂ = 1.6 Hz, 1 H), 3.10 (br s, 1 H), 7.20-7.23 (m, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 13.97, 22.44, 24.60, 29.13, 31.58, 37.95, 44.86, 106.61, 147.16. IR (CCl₄): 3598, 3395, 1722, 1601 cm^-1. Anal. Calcd for C₉H₁₇NO₂ (171.24): C, 63.13; H, 10.01. Found: C, 63.28; H, 9.75.

20

The reaction proceeded less smoothly under elevated temperatures or in the presence of acidic or basic catalysts.